US12384790B2ActiveUtilityA1
Pteridinone compounds and uses thereof
Est. expiryApr 24, 2038(~11.8 yrs left)· nominal 20-yr term from priority
Inventors:David J. LaufferGuy BemisMichael BoydDavid DeiningerHongbo DengWarren DorschWenxin GuRussell R. HooverMac Arthur Johnson, Jr.Mark LedeboerBrian LedfordFrancois MaltaisMarina PenneyDarin TakemotoNathan D. WaalTiansheng WangPan Li
C07D 471/04C07D 498/04C07D 471/14C07D 519/00C07D 487/14C07D 491/20C07D 487/04A61P 35/00C07D 475/04
76
PatentIndex Score
0
Cited by
28
References
20
Claims
Abstract
The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof for treating cellular proliferative disorders (e.g., cancer).
Claims
exact text as granted — not AI-modifiedWe claim:
1. A method for inducing ER stress in a patient in need thereof, comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, indanyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-8 membered saturated or partially unsaturated bridged bicyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is a covalent bond or a C1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein one to three methylene units of the chain are independently and optionally replaced with -Cy-, —O—, —C(R) 2 —, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D) 2 -, —C(F) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O) 2 —, or —Si(R) 2 —, wherein -Cy- is an optionally substituted bivalent group selected from phenylenyl, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl, piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl;
R 1 is hydrogen;
each of R 2 and R 2′ is independently hydrogen, R D , or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
R 2 and R 2′ are optionally taken together to form ═CH 2 or ═CH—(C 1-3 aliphatic);
R 3 is hydrogen, R D , or an optionally substituted C 1-6 aliphatic group;
R 4 is R D , —CD 2 OH, or an optionally substituted C 1-3 aliphatic group;
R 5 is hydrogen, —C(O)R, —C(O)OR, —C(O)NR 2 , an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a C 1-3 aliphatic group;
each of R 6 is independently halogen, —CN, —NO 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —NR 2 , —NRC(O)R, —NRC(O)OR, —NRS(O) 2 R, —OR, —P(O)R 2 , —SR, —SF 5 , —S(CF 3 ) 5 , —S(O)R, —S(O) 2 R, —S(O)(NH)R, —C(═NR)—OR, —O—C(═NR)—R, or R; or
two R 6 groups are optionally taken together to form ═O;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups;
R D is a C 1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
X is N or CH; and
n is 0, 1, 2, 3, 4 or 5,
wherein said patient has a cancer selected from the group consisting of astrocytoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, germ cell cancer, glioblastoma, glioma, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, mesothelioma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, and uterine cancer.
2. The method of claim 1 , wherein the ER stress is induced by causing calcium release from the ER via the Ca2+channel WFS1.
3. The method of claim 1 , wherein Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
4. The method of claim 1 , wherein Ring A is phenyl.
5. The method of claim 1 , wherein Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
6. The method of claim 1 , wherein Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
7. The method of claim 1 , wherein Ring A is
8. The method of claim 1 , wherein L is a C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein one to three methylene units of the chain are independently and optionally replaced with -Cy-, —O—, —C(R) 2 —, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D) 2 -, —C(F) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O) 2 —, or —Si(R) 2 —.
9. The method of claim 8 , wherein -Cy- is an optionally substituted bivalent group selected from cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, or cyclohexylenyl.
10. The method of claim 8 , wherein -Cy- is an optionally substituted bivalent group selected from furylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl, or thiazolylenyl.
11. The method of claim 1 , wherein L is a covalent bond.
12. The method of claim 1 , wherein the compound is of one of formula VI-a, VI-b, VI-c, or VI-d:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is of one of formula VI′-a, VI′-b, VI′-c, or VI′-d:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein:
R 2 is unsubstituted C 1-6 aliphatic, or R D ;
wherein one of R 6 is —CF 3 ; n′ is 1, 2, 3, or 4; and n″ is 1, 2, or 3;
or
or wherein n′″ is 0, 1, 2, or 3.
15. The method of claim 13 , wherein R 2 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , wherein one or more hydrogens are optionally replaced by deuterium.
16. The method of claim 14 , wherein
17. The method of claim 13 , wherein the compound is of one of Formula VIII′-a, VIII′-b, or VIII′-c:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein R 2 is unsubstituted C 1-6 aliphatic.
19. The method of claim 1 , wherein R 3 is hydrogen or an optionally substituted C 1-6 aliphatic group.
20. A method for inducing ER stress in a patient in need thereof, comprising administering to said patient a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof,
wherein said patient has a cancer selected from the group consisting of astrocytoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophagus cancer, germ cell cancer, glioblastoma, glioma, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, mesothelioma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, and uterine cancer.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.